ABCMdb

ABCC2 p.Ala404Thr

Predicted by SNAP2:	C: N (61%), D: D (80%), E: D (80%), F: D (80%), G: D (66%), H: D (80%), I: D (63%), K: D (80%), L: D (71%), M: D (59%), N: D (71%), P: D (75%), Q: D (75%), R: D (80%), S: N (82%), T: N (72%), V: D (59%), W: D (85%), Y: D (80%),
Predicted by PROVEAN:	C: D, D: D, E: D, F: D, G: D, H: D, I: D, K: D, L: D, M: D, N: D, P: D, Q: D, R: D, S: N, T: D, V: D, W: D, Y: D,

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[hide] Xenobiotic, bile acid, and cholesterol transporter... Pharmacol Rev. 2010 Mar;62(1):1-96. Epub 2010 Jan 26. Klaassen CD, Aleksunes LM
Xenobiotic, bile acid, and cholesterol transporters: function and regulation.
Pharmacol Rev. 2010 Mar;62(1):1-96. Epub 2010 Jan 26., [PMID:20103563]

Abstract [show]
Transporters influence the disposition of chemicals within the body by participating in absorption, distribution, and elimination. Transporters of the solute carrier family (SLC) comprise a variety of proteins, including organic cation transporters (OCT) 1 to 3, organic cation/carnitine transporters (OCTN) 1 to 3, organic anion transporters (OAT) 1 to 7, various organic anion transporting polypeptide isoforms, sodium taurocholate cotransporting polypeptide, apical sodium-dependent bile acid transporter, peptide transporters (PEPT) 1 and 2, concentrative nucleoside transporters (CNT) 1 to 3, equilibrative nucleoside transporter (ENT) 1 to 3, and multidrug and toxin extrusion transporters (MATE) 1 and 2, which mediate the uptake (except MATEs) of organic anions and cations as well as peptides and nucleosides. Efflux transporters of the ATP-binding cassette superfamily, such as ATP-binding cassette transporter A1 (ABCA1), multidrug resistance proteins (MDR) 1 and 2, bile salt export pump, multidrug resistance-associated proteins (MRP) 1 to 9, breast cancer resistance protein, and ATP-binding cassette subfamily G members 5 and 8, are responsible for the unidirectional export of endogenous and exogenous substances. Other efflux transporters [ATPase copper-transporting beta polypeptide (ATP7B) and ATPase class I type 8B member 1 (ATP8B1) as well as organic solute transporters (OST) alpha and beta] also play major roles in the transport of some endogenous chemicals across biological membranes. This review article provides a comprehensive overview of these transporters (both rodent and human) with regard to tissue distribution, subcellular localization, and substrate preferences. Because uptake and efflux transporters are expressed in multiple cell types, the roles of transporters in a variety of tissues, including the liver, kidneys, intestine, brain, heart, placenta, mammary glands, immune cells, and testes are discussed. Attention is also placed upon a variety of regulatory factors that influence transporter expression and function, including transcriptional activation and post-translational modifications as well as subcellular trafficking. Sex differences, ontogeny, and pharmacological and toxicological regulation of transporters are also addressed. Transporters are important transmembrane proteins that mediate the cellular entry and exit of a wide range of substrates throughout the body and thereby play important roles in human physiology, pharmacology, pathology, and toxicology.

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6427 Nucleotide Change Amino Acid Change In Vitro Function Protein Expression/Localization SLCO1A2 OATP1A2 T38C I13T 1↔ Normal A382T N128Y ↔ N.D. A404T N135I 2↔ N.D. C502T R168C 2 N.D. A516C E172D 2 Intracellular G559A A187T 2 Normal A833- Asn278STOP 2 N.D. C2003G T668S ↔ Intracellular SLCO1B1 OATP1B1 T217C F73L 2 Intracellular T245C V82A 2 Intracellular A388G N130D 2↔ Normal A452G N151S N.D. N.D. C463A P155T ↔ Normal A467G E156G 2 Normal T521C V174A 2 Intracellular/normal T578G L193R 2 Intracellular C1007G P336R N.D. N.D. T1058C I353T 2 Intracellular A1294G N432D 2↔ Normal A1385G D462G ↔ Normal G1454T C485F N.D. N.D. G1463C G488A 2 Intracellular T1628G L543W N.D. N.D. A1964G D655G 2↔ Normal A2000G E667G 2↔ Normal SLCO1B3 OATP1B3 T334G S112A 1↔ Normal G699A M233I ↔ Normal G1564T G522C 2↔ Reduced G1748A G583E 2↔ Reduced 2, reduced function; 1, increased function; ↔, no change in function; N.D. not determined. ions. Login to comment
6426 Nucleotide Change Amino Acid Change In Vitro Function Protein Expression/Localization SLCO1A2 OATP1A2 T38C I13T 1࢒ Normal A382T N128Y ࢒ N.D. A404T N135I 2࢒ N.D. C502T R168C 2 N.D. A516C E172D 2 Intracellular G559A A187T 2 Normal A833- Asn278STOP 2 N.D. C2003G T668S ࢒ Intracellular SLCO1B1 OATP1B1 T217C F73L 2 Intracellular T245C V82A 2 Intracellular A388G N130D 2࢒ Normal A452G N151S N.D. N.D. C463A P155T ࢒ Normal A467G E156G 2 Normal T521C V174A 2 Intracellular/normal T578G L193R 2 Intracellular C1007G P336R N.D. N.D. T1058C I353T 2 Intracellular A1294G N432D 2࢒ Normal A1385G D462G ࢒ Normal G1454T C485F N.D. N.D. G1463C G488A 2 Intracellular T1628G L543W N.D. N.D. A1964G D655G 2࢒ Normal A2000G E667G 2࢒ Normal SLCO1B3 OATP1B3 T334G S112A 1࢒ Normal G699A M233I ࢒ Normal G1564T G522C 2࢒ Reduced G1748A G583E 2࢒ Reduced 2, reduced function; 1, increased function; ࢒, no change in function; N.D. not determined. ions. Login to comment

[hide] Pharmacogenetics of opioids. Clin Pharmacol Ther. 2007 Mar;81(3):429-44. Somogyi AA, Barratt DT, Coller JK
Pharmacogenetics of opioids.
Clin Pharmacol Ther. 2007 Mar;81(3):429-44., [PMID:17339873]

Abstract [show]
Opioids are used for acute and chronic pain and dependency. They have a narrow therapeutic index and large interpatient variability in response. Genetic factors regulating their pharmacokinetics (metabolizing enzymes, transporters) and pharmacodynamics (receptors and signal transduction elements) are contributors to such variability. The polymorphic CYP2D6 regulates the O-demethylation of codeine and other weak opioids to more potent metabolites with poor metabolizers having reduced antinociception in some cases. Some opioids are P-glycoprotein substrates, whereas, ABCB1 genotypes inconsistently influence opioid pharmacodynamics and dosage requirements. Single-nucleotide polymorphisms in the mu opioid receptor gene are associated with increasing morphine, but not methadone dosage requirements and altered efficacy of mu opioid agonists and antagonists. As knowledge regarding the interplay between genes affecting opioid pharmacokinetics including cerebral kinetics and pharmacodynamics increases, our understanding of the role of pharmacogenomics in mediating interpatient variability in efficacy and side effects to this important class of drugs will be better informed. Opioid drugs as a group have withstood the test of time in their ability to attenuate acute and chronic pain. Since the isolation of morphine in the early 1800s by Friedrich Serturner, a large number of opioid drugs beginning with modification of the 4,5-epoxymorphinan ring structure were developed in order to improve their therapeutic margin, including reducing dependence and tolerance, ultimately without success.

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173 Of these polymorphisms, the variants A516C and A404T demonstrated markedly reduced uptake capacity for deltorphin II and DPDPE. Login to comment